Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling.

Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for γ-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme-substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.

Corrigendum: Case Report: A False Negative Case of Anti-Yo Paraneoplastic Myelopathy.

[This corrects the article DOI: 10.3389/fneur.2021.728700.].

Case Report: A False Negative Case of Anti-Yo Paraneoplastic Myelopathy.

The development of autoimmune antibody panels has improved the diagnosis of paraneoplastic neurological disorders (PNDs) of the brain and spinal cord. Here, we present a case of a woman with a history of breast cancer who presented with a subacute sensory ataxia that progressed over 18 months. Her examination and diagnostic studies were consistent with a myelopathy. Metabolic, infectious, and autoimmune testing were non-diagnostic. However, she responded to empirical immunosuppression, prompting further workup for an autoimmune etiology. An unbiased autoantibody screen utilizing phage display immunoprecipitation sequencing (PhIP-Seq) identified antibodies to the anti-Yo antigens cerebellar degeneration related protein 2 like (CDR2L) and CDR2, which were subsequently validated by immunoblot and cell-based overexpression assays. Furthermore, CDR2L protein expression was restricted to HER2 expressing tumor cells in the patient's breast tissue. Recent evidence suggests that CDR2L is likely the primary antigen in anti-Yo paraneoplastic cerebellar degeneration, but anti-Yo myelopathy is poorly characterized. By immunostaining, we detected neuronal CDR2L protein expression in the murine and human spinal cord. This case demonstrates the diagnostic utility of unbiased assays in patients with suspected PNDs, supports prior observations that anti-Yo PND can be associated with isolated myelopathy, and implicates CDR2L as a potential antigen in the spinal cord.

Triglyceride-glucose index is associated with early neurological deterioration in single subcortical infarction: Early prognosis in single subcortical infarctions.

BACKGROUND: The research about the influence of triglyceride-glucose index on early prognosis in stroke is lacking. AIMS: In this study, we evaluated the association between triglyceride-glucose index and early neurological deterioration in patients with single subcortical infarctions. METHODS: Consecutive patients with single subcortical infarctions within 72 h of symptom onset between 2011 and 2015. Early neurological deterioration was defined as an increase of ≥2 in the total NIHSS score or ≥1 in the motor NIHSS score. The triglyceride-glucose index was calculated using the log scale of fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2. RESULTS: A total of 305 patients with single subcortical infarctions were evaluated. In multivariable analysis, the triglyceride-glucose index (adjusted odds ratio [aOR] = 2.94, 95% confidence interval [CI] = 1.58-5.45) and age (aOR = 1.05, 95% CI = 1.01-1.09) were associated with early neurological deterioration. In subgroup analysis according to the type of single subcortical infarctions, only patients with proximal single subcortical infarctions showed a significant association between the triglyceride-glucose index and early neurological deterioration (aOR = 2.92, 95% CI = 1.35-6.29). On the other hand, there was no statistical significance in patients with distal single subcortical infarctions. Patients with untreated diabetes also showed the close association between the triglyceride-glucose index and early neurological deterioration (aOR = 3.94, 95% CI = 1.47-10.52). CONCLUSIONS: The triglyceride-glucose index was associated with early neurological deterioration in single subcortical infarctions. This association differed depending on the location of lesion and the presence of untreated diabetes.

Peripheral Vasculitic Neuropathy Associated With Minocycline Use.

We describe 2 patients presenting with multiplex mononeuritis, associated with skin manifestation, secondary to minocycline-induced vasculitis. One of the cases is associated neither with lupus nor polyarteritis nodosa. An extensive laboratory workup ruled out any possible underlying immunologic disorder. Electrodiagnostic studies were conducted to show axonal neuropathy in patchy and multifocal distribution consistent with multiplex mononeuritis. This diagnosis was confirmed with nerve biopsy. Withdrawing from the offending medication, minocycline, improved the patients' clinical condition and the quantitative serological measures.

Fabrication and characterization of patterned single-crystal silicon nanolines.

This letter demonstrates a method for fabricating single-crystal Si nanolines, with rectangular cross sections and nearly atomically flat sidewalls. The high quality of these nanolines leads to superb mechanical properties, with the strain to fracture measured by nanoindentation tests exceeding 8.5% for lines of 74 nm width. A large displacement burst before fracture was observed, which is attributed to a buckling mechanism. Numerical simulations show that the critical load for buckling depends on the friction at the contact surface.

Pharmacokinetics of oltipraz in mutant Nagase analbuminemic rats.

Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (50 mg/kg) administration to control male Sprague-Dawely rats and mutant Nagase analbuminemic rats (NARs). In NARs, the expression and mRNA level of CYP1A2 increased, and oltipraz was mainly metabolized via CYP1A1/2, 2B1/2, 2C11, 201, and 3A1/2 in male rats. Hence, it may be expected that the CL of oltipraz would be significantly faster in NARs. This was proven by the following results. After intravenous administration, the CL of oltipraz was significantly faster in NARs (125% increase) than controls due to significantly greater free fractions (unbound to plasma proteins) of oltipraz (197% increase) and significantly faster CL(int) for the disappearance of oltipraz (11.4% increase) in NARs, since oltipraz is an intermediate hepatic extraction ratio drug in rats. The V(ss) was significantly larger in NARs (109% increase) and this could be due to significant increase in free fractions of oltipraz in NARs. After oral administration, the AUC of oltipraz was also significantly smaller in NARs (61.9% decrease). This could also be due to significant increase in free fractions of oltipraz and significantly faster CL(int) in NARs. However, this was not due to decrease in absorption in NARs.

Torsional vibrations of circular elastic plates with thickness steps.

This paper presents a theoretical study of torsional vibrations in isotropic elastic plates. The exact solutions for torsional vibrations in circular and annular plates are first reviewed. Then, an approximate method is developed to analyze torsional vibrations of circular plates with thickness steps. The method is based on an approximate plate theory for torsional vibrations derived from the variational principle following Mindlin's series expansion method. Approximate solutions for the zeroth- and first-order torsional modes in the circular plate with one thickness step are presented. It is found that, within a narrow frequency range, the first-order torsional modes can be trapped in the inner region where the thickness exceeds that of the outer region. The mode shapes clearly show that both the displacement and the stress amplitudes decay exponentially away from the thickness step. The existence and the number of the trapped first-order torsional modes in a circular mesa on an infinite plate are determined as functions of the normalized geometric parameters, which may serve as a guide for designing distributed torsional-mode resonators for sensing applications. Comparisons between the theoretical predictions and experimental measurements show close agreements in the resonance frequencies of trapped torsional modes.